Adjunctive tianeptine treatment for bipolar disorder: A 24-week randomized, placebo-controlled, maintenance trial.

OBJECTIVE: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. METHODS: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. RESULTS: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. CONCLUSION: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.

Daytime sleepiness, sleep disturbance and functioning impairment in bipolar disorder.

OBJECTIVE: To verify the prevalence and clinical impact of excessive daytime sleepiness (EDS) in outpatients with bipolar disorder. METHODS: Eighty-one outpatients with bipolar disorder and 79 healthy control subjects were recruited. Patients were required not to be acutely manic or depressed. We used the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index and the Functioning Assessment Short Test to assess sleepiness, sleep problems and functioning, respectively. RESULTS: Patients had a higher prevalence of sleepiness (40%) than the control group (18%). Sleepiness and sleep disturbance had independent impacts on disability in the multivariable model. CONCLUSIONS: This study suggests that EDS is a relevant clinical dimension in patients with bipolar disorder. It is a frequent symptom that often overlaps with other sleep disturbances. This study also reveals that once present it has the potential to increase functional impairment.

Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity.

Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person's life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with downstream alterations of inflammatory immune processes regulate by cytokines, impaired antioxidant defense and increased lipid peroxidation. The aim of this study was to examine serum oxidative stress markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at early stage (within first 10 years of a psychotic episode), 39 at late stage (minimum 10 years after diagnosis of SZ) and their respective matched controls were included. Each subject had 5 ml blood samples collected by venipuncture to examined thiobarbituric acid-reactive substances (TBARS), total reactive antioxidant potential (TRAP), protein carbonyl content (PCC), Interleukins 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha (TNF-alpha). TBARS, IL-6 and PCC levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP and TNF-alpha levels in patients with SZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage and a decrease trend in early stage was found. Results provided evidence consistent with comparable biological markers across chronic SZ. The concept of biochemical staging proposed by others for bipolar disorder is not seen in this cohort of patients with SZ, at least for cytokines and oxidative stress markers. Our findings reinforce the need of assessment of individuals in ultra high risk to develop psychosis and first-episode population.

A bidimensional solution for outcomes in bipolar disorder.

Although depressive symptoms have been consistently associated with lower quality of life and increased disability in bipolar disorder, their relation to manic symptoms is not as clear cut. A great overlap between these outcomes complicates the understanding of how they cluster together. We used exploratory factor analysis to clarify the relation between these constructs. We consecutively recruited 320 patients with bipolar disorder, and interviewers rated the Hamilton Depression and Anxiety Rating Scales, the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI), and the Global Assessment of Functioning (GAF). The self-rated Sheehan Disability Scale and the World Health Organization Quality of Life-BREF questionnaires were also collected. Two distinct and large dimensions emerged. Depression and anxiety, along with the self-rated scales, loaded in the first factor, whereas the YMRS, the GAF, and the CGI loaded in the second. These findings imply that evaluating self- and observer-rated outcomes may make up for a more thorough evaluation because each conveys unique illness information.

Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes.

Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity. Previous studies demonstrated that neurotrophin-3 (NT-3) plays a role in the pathophysiology of mood disorders. The influence of medication in these studies has been considered a limitation. Thus, studies with drug-free vs. medicated patients are necessary to evaluate the role of medication in serum NT-3 levels. About 10 manic and 10 depressive drug-free, and 10 manic and 10 depressive medicated patients with BD type I were matched with 20 controls for sex and age. Patients were assessed using SCID-I, YMRS and HDRS. Serum NT-3 levels in drug-free and medicated patients is increased when compared with controls (2.51+/-0.59, 2.56+/-0.44 and 1.97+/-0.33, respectively, p<0.001 for drug-free/medicated vs. control). Serum NT-3 levels do not differ between medicated and drug-free patients. When analyzing patients according to mood states, serum NT-3 levels are increased in both manic and depressive episodes, as compared with controls (2.47+/-0.43, 2.60+/-0.59 and 1.97+/-0.33, respectively, p<0.001 for manic/depressive patients vs. controls). There is no difference in serum BDNF between manic and depressive patients. Results suggest that increased serum NT-3 levels in BD are likely to be associated with the pathophysiology of manic and depressive symptoms.

Functional impact of biological rhythm disturbance in bipolar disorder.

Bipolar disorder (BD) is characterized by frequent recurrence, incomplete recovery, cognitive dysfunction and poor functioning. Impairment lingers in the interepisodic period and mechanisms leading to this dysfunctional state are not fully comprehended. To our knowledge the association of biological rhythm dysfunction with functioning in BD has not been assessed directly. The objective of this study was to measure and quantify the impact of rhythm dysfunction on interepisodic functioning in BD. We also tested the association between executive functioning and sleep and rhythm problems. Eighty-one outpatients with BD and 79 matched control subjects were consecutively recruited. Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and biological rhythms with the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). A subsample had their executive functioning assessed with the Wisconsin Card Sorting Test (WCST). Patients and control subjects were well matched. Functioning and rhythm scores were correlated in patients and control subjects. The BRIAN score was the strongest predictor of functioning in the regression model. Biological rhythms partially mediated the impairment associated with bipolar disorder. The rhythm score was also associated with executive functioning. Biological rhythm dysfunction was a potent predictor of functioning in interepisodic patients with bipolar disorder; it may also mediate much of the disorder-induced disability. These results further the notion that biological rhythms may be interesting targets for diverse interventions aiming to improve functioning and prevent relapse in interepisodic bipolar disorder.

3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder.

BACKGROUND: There has been an increasing interest in the role of oxidative stress in the pathophysiology of bipolar disorder. To explore this further, we evaluated the activity of glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST), as well as 3-nitrotyrosine levels and carbonyl content in patients in the early (within 3 years of illness onset) and late (a minimum of 10 years of illness) stages of bipolar disorder. METHODS: We matched 30 patients in the early stage and 30 patients in the late stage of bipolar disorder, diagnosed according to DSM-IV criteria, with 60 healthy controls (30 matched for each group of patients). We measured symptomatic status using the Hamilton Rating Scale for Depression and the Young Mania Rating Scale. RESULTS: We found a significant increase in 3-nitrotyrosine levels among patients in the early (p < 0.010) and late (p < 0.010) stages of bipolar disorder. The activity of GR and GST was increased only among patients in the late stage of illness. Glutathione peroxidase activity and carbonyl content did not differ among the groups. LIMITATIONS: Limitations of our study include its cross-sectional design, which did not allow us to examine direct causative mechanisms or the effects of progression of illness, and the potential environmental bias introduced by comparing patient groups recruited from different regions of the world. CONCLUSION: Our data indicate a possible tyrosine nitration-induced damage in patients with bipolar disorder that is present from the early stage of illness. Our data also indicate that patients in the late stage of illness demonstrate enhanced activity of GR and GST, which could suggest the involvement of a compensatory system in bipolar disorder.

Sleep in bipolar patients.

BACKGROUND: Sleep disturbance has been described in bipolar disorder (BPD). Specific complaints may include frequent nighttime awakenings, poor quality of sleep, reduction in total sleep time, and nightmares. Most patients with BPD also report insomnia when in depression, but a significant percentage of patients report hypersomnia symptoms with prolonged nighttime sleep, difficulty in wakening, and excessive daytime sleepiness. OBJECTIVES: The present study aims to investigate whether bipolar patients with sleep disorders presented impairment in quality of life, disability, and global function. METHODS: One hundred ninety bipolar patients type-I diagnosed by application of Structured Clinician Interview for DSM-IV Disorders (SCID), were distributed in two groups based on absence or presence of sleep disorders. Quality of life, disability, and global dysfunction were evaluated using the Health Organization's Quality of Life instrument (WHOQOL-Brief), the Sheehan Disability Scale, and the Global Assessment of Functioning (GAF), respectively. RESULTS: Sleep complaints have negative influence on general quality of life, observed by decreased scores in WHOQOL and GAF domains and increased Sheehan scores, indicating the importance of maintenance of normal sleep in bipolar patients. CONCLUSION: Our results suggest that sleep complains impair quality of life and global function. Collectively, further studies are warranted to investigate the impairment of sleep disturbance on others neurotrophic factors and neurochemical pathways.

Increased serum neurotrophin-4/5 levels in bipolar disorder.

Neurotrophins are central to several aspects of central nervous system function, and emerging evidence links these growth factors to mood disorders. The purpose of this study was to investigate serum neurotrophin-4/5 (NT-4/5) levels in patients with bipolar disorder, both within mood episodes and in euthymia. Patients with bipolar I disorder (n=154) and controls (n=30) had their NT-4/5 serum levels assayed using an ELISA. Levels of NT-4/5 levels were significantly higher in bipolar disorder patients than in controls; NT-4/5 levels were increased in mania, depression and euthymia, but not significantly different between BD mood states. As far as are aware, this is the first study showing NT-4/5 immunocontent alterations in bipolar disorder. A tentative explanation would be that NT-4/5 increases is compensating for ongoing oxidative damage in dopaminergic neurons.

Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania.

It has been demonstrated that lithium (Li) and valproate (VPT), first line mood stabilizers, increase BDNF content in rat hippocampus and frontal cortex, which suggests that the regulation of neurotrophic factors might be associated with their pharmacological effects. In sight of the scarcity of studies with other neurotrophins, and the possible relevance of multiple neurotrophic signaling systems in bipolar disorder we investigated the effects of Li and VPT on NT-3 levels in rat serum and hippocampus, using an animal model of mania induced by amphetamine (AMPH). In the reversal model, adult male Wistar rats received AMPH or saline for 14 days, and between the 8th and 14th days, animals were treated with Li, VPT or saline. In the prevention model, rats were pretreated with Li, VPT or saline, and between the 8th and 14th days, the animals received AMPH or saline. Li increased serum and hippocampal NT-3 levels in all conditions, whereas VPT increased hippocampal NT-3 in the prevention model only. Li reversed AMPH changes in NT-3 in the reversal model, and VPT prevented AMPH changes in NT-3 in the prevention model. These results suggest that both Li and VPT modulate serum and central (hippocampal) NT-3 levels, and further support that the regulation of neurotrophic signaling systems may be related to the mechanisms of action of mood stabilizers.

Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder.

Accumulating evidence suggest that neural changes and cognitive impairment may accompany the course of bipolar disorder. Such detrimental effects of cumulative mood episodes may be related to changes in neurotrophins that take place during mood episodes but not during euthymic phases. The present study investigated serum neurotrophin-3 (NT-3) levels in patients with bipolar disorder during manic, depressed, and euthymic states, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum NT-3 levels were increased in manic (p<0.001) and depressed (p<0.001) BD patients, as compared with euthymic patients and normal controls. These findings suggest that the NT-3 signaling system may play a role in the pathophysiology of BD.